T. A. Miano, A. Ganetsky, D. L. Porter, R. Reshef; University of Pennsylvania, Philadelphia, PA

BACKGROUND: Tacrolimus (TAC) is commonly used for prevention of graft vs. host disease after Hematopoeitic Stem Cell Transplant. Due to its narrow therapeutic index, WC is monitored to guide dosing. TAC is 85-95% bound to hemoglobin (HGB); thus, changes in HGB levels could alter the relationship between WC and free TAC concentration. This is of particular relevance after HSCT, given the myelosuppression from chemotherapy. This study aimed to quantify the relationship between HGB and TAC-WC.
METHODS: This was a retrospective cohort analysis of 79 patients who underwent a uniform HSCT procedure. Eligible patients were free of significant organ dysfunction and uncontrolled infection. We collected TAC dose, TAC-WC, interacting drugs, demographics, and disease variables. TAC daily dose, TAC-WC, and HGB were averaged at weekly intervals. Change in HGB was stratified by baseline HGB (above vs. below the median). The relationship between HGB levels and TAC-WC was modeled with a mixed-effects model.
RESULTS: Mean (range) HGB at baseline was 9.8 mg/dL (7.2-13.0), and decreased by week 2: 8.9 mg/dL (7.4-11.3), p<0.001. The decrease in HGB was greater in those with baseline HGB above median (1.17 mg/dL) vs. those below (0.60 mg/dL), p<0.001. HGB values increased from week 2- week 4, as patients engrafted with donor hematopoiesis: 10.1 (7.7-12.3), p<0.001. Changes in HGB were predictive of TAC-WC: a one-unit change in HGB was associated with a 0.73 mg/dL (0.47-1.1) change in TAC-WC, p<0.001. The estimate was similar after adjusting for covariates: 0.71 mg/dL (0.43-0.98), p<0.001.
CONCLUSION: Differences in HGB are associated with significant differences in TAC-WC, implying that TAC-WC may under- or over-estimate free drug exposure. Future studies that examine the effects of HGB on the efficacy and toxicity of TAC are warranted.